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Theory notes

Calcium is required for the proper functioning of muscle contraction, nerve conduction, hormone release, and blood coagulation. In addition,calcium is required as a cofactor for various enzymes.

Calcium balance

Calcium is an important nutrient. The daily intake is approximately 1000 mg/day. The adult human body contains approximately 1100 g (27.5mol) of calcium. 99% of the calcium is in bone. Blood calcium levels are normally 9-10.2 mg/dL (2.25-2.55mmol/L).Of the total amount, 50% is free ionized calcium, 10% is combined with various anions (including bicarbonate, citrate, phosphate, lactate and sulphate) and the remaining 40% is bound to serum proteins mainly albumin. Free ionized calcium is the physiologically important component of the total calcium. In plasma, the ionized calcium concentration is normally maintained within a tight range (1.0-1.25mmol/l).

Intestinal absorption

30-80% of ingested calcium is absorbed, primarily in the upper small intestine. Absorption is related to calcium intake. If intake is low, active transcellular calcium transport in the duodenum is increased and a larger proportion of calcium is absorbed by the active process compared with the passive paracellular process that occurs in the jejunum and ileum.

Vitamin D is important for the active process. Active calcium transport depends on the presence in the intestinal cell of calbindin protein, the biosynthesis of which is totally dependent on vitamin D. Passive absorption in the jejunum and ileum predominates when dietary calcium intake is adequate or high.

Calcium reaching the large intestine is absorbed by active and passive processes. Usually, no more than 10% of total absorption takes place in the large intestine, but this site becomes nutritionally important in conditions of significant small bowel resection.

Calcium absorption is inhibited by phosphates and oxalates because these anions form insoluble salts with calcium in the intestine.

Physiological functions of calcium

Calcium plays a central role in a number of physiological processes that are essential for life. Calcium is necessary for several physiological processes including neuromuscular transmission, smooth and skeletal muscle contraction, cardiac automaticity, nerve function, cell division and movement, and certain oxidative processes. It is also a co-factor for many steps during blood coagulation. Intracellular calcium is involved as a second messenger in many intracellular responses to chemical and electrical stimuli and required by many enzymes for full activity. Many different calcium binding proteins have been described, but the two with well established functions are troponin and calmodulin. Troponin is involved in muscle contraction, whereas calmodulin causes configurational changes to proteins and enzyme activation. Ca is also involved in the action of other intracellular messengers, such as cyclic adenosine monophosphate (cAMP) and inositol 1,4,5-triphosphate, and thus mediates the cellular response to numerous hormones, including epinephrine, glucagon, ADH (vasopressin), secretin, and cholecystokinin. 

Intracellular calcium levels are much lower than the extracellular, due to relative membrane impermeability and membrane pumps employing active transport. Calcium entry via specific channels leads to direct effects, e.g. neurotransmitter release in neurons, or further calcium release from intracellular organelles, e.g. in cardiac and skeletal muscle.

Despite its important intracellular role, roughly 99% of body Ca is in bone, mainly as hydroxyapatite crystals. Roughly 1% of bone Ca is freely exchangeable with the ECF and, therefore, is available for buffering changes in Ca balance.

Influences on calcium concentration

Total plasma calcium value varies with the plasma concentration. Since a significant proportion of calcium in the blood is bound to albumin, it is important to know the plasma albumin concentration when evaluating the total plasma calcium.  Ionized calcium level increases with acidosis, and decreases with alkalosis.

Regulation of calcium homeostasis

The metabolism of Ca and of PO4 is intimately related.

Three principal hormones are involved in calcium homeostasis, acting at three target organs, the intestine, bone and kidneys:

1) Vitamin D

Vitamin D, a fat soluble vitamin, is produced by the action of ultraviolet light. Vitamin D3 (Cholecalciferol) is produced by the action of sunlight and is converted to 25-hydroxycholecalciferol in the liver. The 25-hydroxy-cholecalciferol is converted in the proximal tubules of the kidneys to the more active metabolite 1,25-dihydroxy-cholecalciferol.(Figure-1) 1,25-dihydroxycholecalceriferol synthesis is regulated in a feedback fashion by serum calcium and phosphate. Its formation is facilitated by parathyroid hormone.

The actions of Vitamin D are as follows:

1. Enhances calcium absorption from the intestine

2. Facilitates calcium absorption in the kidney

3. Increases bone calcification and mineralization

4. In excess, mobilizes bone calcium and phosphate

2) Parathyroid hormone (PTH)

Parathyroid hormone is a linear polypeptide containing 84 amino acid residues. It is secreted by the chief cells in the four parathyroid glands. Plasma ionized calcium acts directly on the parathyroid glands in a feedback manner to regulate the secretion of PTH. In hypercalcaemia, secretion is inhibited, and the calcium is deposited in the bones. In hypocalcaemia, parathyroid hormone secretion is stimulated. The actions of PTH are aimed at raising serum calcium.

1. Increases bone resorption by activating osteoclastic activity

2. Increases renal calcium reabsorption by the distal renal tubules

3. Increases renal phosphate excretion by decreasing tubule phosphate reabsorption

4. Increases the formation of 1,25-dihydrocholecalciferol by increasing the activity of alpha-1-hydroxylase in the kidney.(Figure-3)

A large amount of calcium is filtered in the kidneys, but 99% of the filtered calcium is reabsorbed. About 60% is reabsorbed in the proximal tubules and the remainder in the ascending limb of the loop of Henle and the distal tubule. Distal tubule absorption is regulated by parathyroid hormone.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure-1- showing  activation of vitamin D

 3. Calcitonin

Calcitonin is a 32 amino acid polypeptide secreted by the parafollicular cells in the thyroid gland. It tends to decrease serum calcium concentration and, in general, has effects opposite to those of PTH. The actions of calcitonin are as follows:

1. Inhibits bone resorption

2. Increases renal calcium excretion

The exact physiological role of calcitonin in calcium homeostasis is uncertain. The effects of calcitonin on bone metabolism are much weaker than those of either PTH or vitamin D.

The calcium-sensing receptor (C ASR)

It is a G protein-coupled receptor that plays an essential part in regulation of extracellular calcium homeostasis. This receptor is expressed in all tissues related to calcium control, i.e. parathyroid glands, thyroid C-cells, kidneys, intestines and bones. By virtue of its ability to sense small changes in plasma calcium concentration and to couple this information to intracellular signalling pathways that modify PTH secretion or renal calcium handling, the CASR plays an essential role in maintaining calcium ion homeostasis.(Figure-2)

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure- 2- A decrease in extracellular (ECF) calcium (Ca2+) triggers an increase in parathyroid hormone (PTH) secretion (1) via activation of the calcium sensor receptor on parathyroid cells. PTH, in turn, results in increased tubular reabsorption of calcium by the kidney (2) and resorption of calcium from bone (2) and also stimulates renal 1,25(OH)2D production (3). 1,25(OH)2D, in turn, acts principally on the intestine to increase calcium absorption (4). Collectively, these homeostatic mechanisms serve to restore serum calcium levels to normal.

Bone and calcium

The calcium in bone exists in two forms: a larger reservoir of stable calcium and a readily exchangeable pool which is about 0.5 to 1% of the total calcium salts and is the first line of defense against changes in plasma calcium. It provides a rapid buffering mechanism to prevent the serum calcium ion concentration in the extracellular fluids from rising to excessive levels or falling to very low levels under transient conditions of excess or  hypo availability of calcium. The other system is mainly concerned with bone remodeling by the constant interplay of bone resorption and deposition, which accounts for 95% of bone formation.

Effects of other hormones on calcium metabolism

Glucocorticoids lower serum calcium levels by inhibiting osteoclast formation and activity, but over long periods they cause osteoporosis by decreasing bone formation and increasing bone resorption. They also decrease the absorption of calcium from the intestine by an anti-vitamin D action and increased its renal excretion. The decrease in serum calcium concentration increases the secretion of parathyroid hormone, and bone resorption is facilitated. Growth hormone increases calcium excretion in the urine, but it also increases intestinal absorption of calcium, and this effect may be greater than the effect on excretion, with a resultant positive calcium balance. Thyroid hormones may cause hypercalcaemia, hypercalciuria, and, in some instances, osteoporosis. Oestrogens prevent osteoporosis, probably by a direct effect on osteoblasts. Insulin increases bone formation, and there is significant bone loss in untreated diabetes.

Key points in calcium homeostasis

1) Calcium homeostasis is regulated by three hormones, parathyroid hormone, vitamin D and calcitonin. The free, ionized calcium concentration is physiologically important for the functions of excitable tissues such as nerve and muscle.

2) Parathyroid hormone increases plasma calcium by mobilizing it from bone, increases reabsorption from the kidney and also increases the formation of 1, 25 dihydroxycholecalciferol.

3) 1,25-dihydroxycholecalciferol increases calcium absorption from the intestine, mobilizes calcium from the bone and increases calcium reabsorption in the kidneys

4) Calcitonin inhibits bone resorption and increases the amount of calcium in the urine, thus reducing plasma calcium

5) The calcium-sensing receptor (CASR) plays an important role in regulation of extracellular calcium.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure-3- showing the role of PTH in maintaining calcium homeostasis

 

Variation of serum Calcium levels

Hypocalcaemia

The causes of hypocalcemia include Hypoalbuminemia, hypomagnesaemia, hyperphosphatemia, multifactorial enhanced protein binding, medication effects, surgical effects, PTH deficiency or resistance, and vitamin D deficiency or resistance. Protein binding is enhanced by elevated pH and free fatty acid release in high catecholamine states. Hypocalcaemia can occur following rapid administration of citrated blood or lavage volume of albumin and in alkalosis caused by hyperventilation. Acute hypocalcaemia can also occur in the immediate post-operative period, following removal of the thyroid or parathyroid glands.

Hypocalcaemia may present with acute symptoms or be asymptomatic. Clinical signs include tetany, carpopedal spasm and laryngeal stridor. Hypocalcaemia may lead to cardiac dysrrhythmias, decreased cardiac contractility, causing hypotension, heart failure or both. Electrocardiographic changes include prolongation of the QT interval. Hypocalcaemia may be accompanied by changes in magnesium concentrations.

Hypercalcaemia

Hypercalcemia is divided into PTH-mediated hypercalcemia (primary hyperparathyroidism) and non–PTH-mediated hypercalcemia.

PTH-mediated hypercalcemia is related to increased calcium absorption from the intestine. Primary hyperparathyroidism originally was the disease of “stones, bones, and abdominal groans.” In most primary hyperparathyroidism cases, the calcium elevation is caused by increased intestinal calcium absorption. This is mediated by the PTH-induced Calcitriol synthesis that enhances calcium absorption. The increase in serum calcium results in an increase in calcium filtration at the kidney. Because of PTH-mediated absorption of calcium at the distal tubule, less calcium is excreted than might be expected.

Non–PTH-mediated hypercalcemia includes the following:

Hypercalcemia associated with malignancy, granulomatous disorders, and metastasis to the bone from breast, multiple myeloma, and hematologic malignancies (Breast cancer is one of the most common malignancies responsible for hypercalcemia.).Causes of hypercalcaemia also include hyperthyroidism, adrenal insufficiency, pheochromocytoma,drug therapy such as thiazides and lithium, and immobilization.

Hypercalcaemia may present with renal problems, polyuria and polydipsia, neuropsychiatric disorders, nausea, vomiting and peptic ulceration. The cardiovascular effects include raised blood pressure, a shortened Q-T interval and dysrrhythmias.

Specific treatment is aimed at the cause, but it may also be necessary to decrease calcium levels by increasing excretion and decreasing bone resorption.

 

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Iron absorption takes place largely in the proximal small intestine and is a carefully regulated process. In general, there is no regulation of the amounts of nutrients absorbed from the gastro intestinal tract. A notable exception is iron, the reason that absorption must be carefully regulated is that the body does not possess a physiological mechanism to eliminate much iron from the body. The small amount of iron that is lost each day (about 1-2 mg) is matched by dietary absorption of iron.

 Mechanism of iron absorption
 Iron is found in the diet  as ionic (non-haem) iron and haem iron. Absorption of these two forms of iron occurs by different mechanisms. Absorption is a multistep process involving the uptake of iron from the intestinal lumen across the apical cell surface of the villus enterocytes and the transfer out of the enterocyte across the basolateral membrane to the plasma. Ionic iron is present in the reduced (ferrous) or oxidised (ferric) state in the diet and the first step in the uptake of ionic iron involves the reduction of iron. Recently, a reductase that is capable of reducing iron from its ferric to ferrous state has been identified. It is a membrane bound haem protein called Dcytb that is expressed in the brush border of the duodenum. Next, ferrous ion is transported across the lumen cell surface by a transporter called divalent metal transporter 1 (DMT1) that can transport a number of other metal ions including copper, cobalt, zinc, and lead.

 

 

 

 

 

 

 

 

 

 

 

 

Figure- Showing the mechanism of iron absorption

 Once inside the gut cell, iron may be stored as ferritin or transported through the cell to be released at the basolateral surface to plasma transferrin through the membrane-embedded iron exporter, ferroportin. The function of ferroportinis negatively regulated by hepcidin,the principal iron regulatory hormone. More the Hepcidin levels lesser is the iron absorption and vice versa. In the process of release, iron interacts with another ferroxidase, hephaestin, which oxidizes the iron to the ferric form for transferrin binding. Hephaestin is similar to ceruloplasmin, the copper-carrying protein.

 The mechanism of absorption of haem iron has yet to be elucidated. Transfer across the brush border membrane is probably mediated by an unidentified haem receptor. Once inside, enterocyte iron is released from haem by haem oxygenase and either stored or transferred out of the enterocyte by a mechanism that is likely to be similar to that for ionic iron

 Factors affecting iron absorption

 Iron absorption is influenced by a number of physiologic states.

 1) Erythroid hyperplasia stimulates iron absorption, even in the face of normal or increased iron stores, and in this state hepcidin levels are inappropriately low. The molecular mechanism underlying this relationship is not known. Thus, patients with anemias associated with high levels of ineffective erythropoiesis absorb excess amounts of dietary iron. Over time, this may lead to iron overload and tissue damage. In iron deficiency, hepcidin levels are low and iron is much more efficiently absorbed from a given diet; the contrary is true in states of secondary iron overload.

 2)  Hypoxia-Both the rate of erythropoiesis and hypoxia regulate iron absorption. Expression of ferroportin and Dcytb are increased in hypoxia, resulting in more iron absorption.

 3)  Body Stores– Iron absorption is stimulated if the levels of  body stores are low. On the contrary, Hepcidin is produced excessively by hepatocytes when iron stores are full, hepcidin makes a complex with ferroportin promoting its degradation and thus iron is not  transported out of the enterocyte in to the blood. Iron  remains inside the cell in the form of ferritin till the life span of the cell

 

 

 

 

 

 

 

 

 

 

  Figure- showing influence of body iron stores on iron absorption

 4)  Inflammation can also stimulate hepcidin production resulting in lowered iron absorption.

 

 

 

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